Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT-β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy.

Detaljer

Författare
  • Hoeke A. Baarsma
  • Wioletta Skronska-Wasek
  • Kathrin Mutze
  • Florian Ciolek
  • Darcy E. Wagner
  • Gerrit John-Schuster
  • Katharina Heinzelmann
  • Andreas Günther
  • Ken R. Bracke
  • Maylis Dagouassat
  • Jorge Boczkowski
  • Guy Brusselle
  • Ron Smits
  • Oliver Eickelberg
  • Ali Oe. Yildirim
  • Melanie Königshoff
Externa organisationer
  • University Hospital Munich
  • Justus Liebig University Giessen
  • Ghent University Hospital
  • Mondor Institute of Biomedical Research (Inserm U955)
  • Erasmus University Medical Center
Originalspråkengelska
Sidor (från-till)143-163
Antal sidor21
TidskriftJournal of Experimental Medicine
Volym214
Utgåva nummer1
StatusPublished - 2017
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa